Syphilis is a sexually transmitted infection that, after five centuries, continues to plague individuals worldwide. Despite the existence of an effective cure, syphilis infection is again epidemic in the United States and in many developing countries. In addition to the serious late sequelae of infection, syphilis is a risk factor for transmission and acquisition of HIV infection, and the clinical course and efficacy of treatment of syphilis is altered in HIV infected patients. In order to control this infection, effective immunization must be developed. This can be approached in a rational way only with a clear understanding of the host's immune response and the antigens that trigger effective mechanisms of immunity. Based upon our earlier studies, we have hypothesized that the resolution of syphilis lesions is mediated by activated macrophages, which, in concert with opsonic antibodies, ingest and kill Treponema pallidum. The aims of this proposal are to define the molecular basis of this immune response. Specifically, we propose to 1)Identify the target antigens for the antibodies that facilitate macrophage-mediated phagocytosis and killing of T. pallidum; 2) Determine the subclasses of IgG and the Fc receptors that induce phagocytosis and killing of 1. pallidum by human monocyte-derived macrophages; 3) Determine the level of macrophage activation necessary for the killing of T. pallidum, and the cytokine or treponemal antigen signals required to achieve such activation; 4) Identify the T. pallidum antigens that directly trigger effective macrophage activity or induce the production of cytokine signals for macrophage activation; and 5) Examine the efficacy and killing of T. pallidum by recognized microbicidal systems. These studies will define the antigenic molecules and specific immunologic functions central to the immune response to syphilis, and will provide a rationale for development of immunization protocols.